DETAILED ACTION
Status of claim rejections
The objections of record to the specification are withdrawn in view of Applicant’s filing of an amended specification in the response filed 05/20/2026.
The objections to the drawings are withdrawn in view of Applicant’s filing of amended drawing sheets in the response filed 05/20/2026.
The objection to claim 1 is withdrawn in view of Applicant’s amendments in the response filed 05/20/2026.
The rejections of record under 35 USC 112(b) are withdrawn in view of Applicant’s amendments in the response filed 05/20/2026.
The rejection of claim 15 under 35 USC 102 is withdrawn in view of Applicant’s cancellation of the claim in the response filed 05/20/2026.
The rejections of record under 35 USC 103 are maintained in view of Applicant’s amendments/arguments in the response filed 05/20/2026.
This Action is FINAL.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/14/2026 was filed after the mailing date of the Non-Final Office Action 02/23/2026. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Maintained Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
First rejection
Claims 1-3 and 5-14 are rejected under 35 U.S.C. 103 as being unpatentable over Lu (prior art of record) in view of Schmidt et al (Enzyme-mediated ligation technologies for peptides and proteins. Curr Opin Chem Biol. 2017 Jun;38:1-7. doi: 10.1016/j.cbpa.2017.01.017. Epub 2017 Apr 20; in 12/27/2023 IDS; hereinafter “Schmidt”).
Lu teaches chemical strategies for synthesis and development of efficient and reproducible methods for convenient preparation of covalently linked peptide-oligonucleotide conjugates (POCs) (see title and abstract), including chemical ligation and enzymatic approaches to creating nucleopeptide POCs (see Fig. 3, 5, and 6; pg. 197; a method of ligation of a (poly)peptide as in claim 1). Lu teaches taking oligonucleotides (i.e., cargo molecule) peptides and conjugating via chemical linkages and bonding, like keto-oxime bonds, oxime bonds, glyoxylic oxime bond, etc. (see Fig. 3-6).
Lu does not explicitly teach that the cargo molecule is modified with a peptide tag, wherein the peptide tag and/or the (poly)peptide comprises a ligation motif for a peptide ligase, wherein the peptide tag is coupled to the cargo molecule via a scaffold comprising phosphoramidite or phosphoramidate group and (ii) contacting the cargo molecule and the (poly)peptide with a peptide ligase that ligates the peptide tag with the (poly)peptide via the ligation motif.
However, Schmidt teaches enzyme-mediated ligation technologies for peptides and proteins (see title, abstract). Schmidt explicitly teaches enzymatic strategies using ligases and peptide tags such as sortase, butelase, peptiligase or omniligase generally feature excellent chemoselectivity, therefore making them valuable tools for protein and peptide chemists (see abstract). Schmidt teaches ligase mediated strategies using sortase and butelase 1, where the polypeptide/peptides contain a sortase or butelase-1 ligation motif (as in claim 1; see light gray rectangle in Fig. 1 and 2 reproduced below) and contacting the peptide with the ligase to ligate the tag with a peptide via the sortase or butelase-1 ligation motifs (as in claim 1; see black and grey ligation catalyzed product in Fig. 1 and 2 below).
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Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of making peptide and oligonucleotide conjugates as taught by Lu with the enzymatic ligation techniques as taught by Schmidt to arrive at the claimed invention. One of ordinary skill would have been motivated to make the modification because Schmidt explicitly teaches that enzymatic strategies using ligases such as sortase, butelase, peptiligase or omniligase generally feature excellent chemoselectivity, and are valuable tools for protein engineering, chemoselective labelling and macrocyclization of peptides and proteins (see pg. 1, col 1).
Furthermore, it would have been prima facie obvious to one of ordinary skill at the time of filing to couple the peptide tag to the cargo via a phosphoramidite or phosphoramidate group, as Lu explicitly teaches the use of using phosphoramidite derivatives capable of introducing aldehyde and glyoxylic aldehyde precursors at 5′-end of the ON (see Fig. 5).
Regarding claim 2, it would have been prima facie obvious to include a peptide tag (such as the one taught by Schmidt in the oligonucleotide as taught by Lu for the same reasons as set forth above.
Regarding claim 3, Schmidt teaches, e.g., LPXTG sortase peptide tag, which is 5 amino acids long (i.e., up to 10 amino acids).
Regarding claim 5, Schmidt teaches the ligation motif is on the C-terminus (see Fig. 1 above).
Regarding claim 6, Schmidt teaches using sortase and butelase (see above).
Regarding claim 7-8, Lu teaches the cargo molecule is oligonucleotides.
Regarding claim 9 and 10, Lu teaches conjugation of peptide to oligonucleotide (ON) mostly occurs at 5′- or 3′-ends of the ON and on 2′-position of the ribose sugar and nucleobases (see pg. 187, col 2).
Regarding claim 11-13, Lu teaches using various oligonucleotide analogues including 2′-O-carboxymethyl ON (as in claim 11) that were obtained by using a novel uridine 3′-phosphoramidite building block (as in claim 12), where the resulting ONs were then efficiently conjugated on a solid support under normal peptide coupling conditions to various amines or to the N-termini of small peptides to give pure products in good yield. (pg. 189, col 1). Lu also teaches using phosphoramidite derivatives capable of introducing aldehyde and glyoxylic aldehyde precursors at 5′-end of the ON. The phosphoramidite derivative #4 depicted in Fig. 5 (which reads on claimed structure (A5)) was prepared in two straight steps starting from 1,2,6-hexane triol and incorporated at the 5′-end of the ON during the solid-phase ON synthesis using the routine coupling procedure (see screenshot below).
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Regarding claim 14, it would have been prima facie obvious to one of ordinary skill at the time of filing to combine ligation motifs of Schmidt for peptide ligase to arrive at the claimed invention. It is prima facie obvious to combine two compositions (the ligation motifs) each of which is taught by the prior art to be useful for the same purpose (advantageous ligation of polypeptides), in order to form a third composition to be used for the very same purpose. “The idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (see MPEP 2144.06).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, especially in the absence of evidence to the contrary.
Response to arguments
Applicant's arguments filed 05/20/2026 have been fully considered but they are not persuasive.
On pg. 16-17 of the remarks, Applicant argues that Lu fails to disclose a peptide tag coupled to a phosphoramidite or phosphoramidate scaffold, incorporation of the scaffold into a cargo molecule, the presence of a ligation motif, or enzymatic ligation of peptides into cargo molecules, and thus fails to disclose the claimed method. Applicant argues a PHOSITA would not have been motivated to modify Lu to arrive at the claimed invention as there is no teaching, suggestion or motivation in Lu that phosphoramidite chemistry could be repurposed to introduce biologically functional peptide ligation motifs or be used to achieve site-specific conjugation. Applicant further argues that Lu is confined to chemical coupling strategies, and that Schmidt fails to cure the deficiencies of Lu. Applicant further urges that the disclosure of Applicant cannot be used to hunt through the prior art for the claimed elements and then combine them. Applicant urges the claimed invention is a not a predictable use of prior art elements but a functional repurposing of phosphoramidite chemistry into a molecular platform for peptide ligation motifs.
In response, the examiner disagrees. First, Lu explicitly teaches a method of chemically ligating polypeptides to make covalently linked peptide-oligonucleotide conjugates (POCs) (see title and abstract), including chemical ligation and enzymatic approaches to creating nucleopeptide POCs (see Fig. 3, 5, and 6; pg. 197), using oligonucleotides as cargo molecules (see above). Second, Lu does not have to teach “repurposing phosphoramidite chemistry to introduce biologically functional peptide ligation otifs, etc.” as argued because Lu explicitly teaches using various oligonucleotide analogues including 2′-O-carboxymethyl ON that were obtained by using a novel uridine 3′-phosphoramidite building block (as in claim 12), where the resulting ONs were then efficiently conjugated on a solid support under normal peptide coupling conditions to various amines or to the N-termini of small peptides to give pure products in good yield. (pg. 189, col 1). Thus, Lu provides a PHOSITA a teaching, suggestion, or motivation to use phosphoramidite to give pure ligated polypeptide product yield. Third, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Before the filing date of the claimed invention, the prior art recognized the advantageous use of phosphoramidites when ligating polypeptides as instantly claimed, without knowledge gleaned from Applicant’s disclosure. Thus, the rejections of record are maintained.
Conclusion
NO CLAIMS ALLOWED.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/G.C.R./Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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